Suicide is the second leading cause of death among youths and has become a major public health concern in the United States. An understanding of the various risk factors, psychosocial, psychological and neurobiological, may result in a better understanding of the pathophysiology of suicide. In turn, this may aid in the identification, treatment and prevention of teenage suicide. Several recent reports suggest increased serotonin-2 receptors in the postmortem brain of suicide victims of suicidal patients. We propose to study 5HT receptor subtypes (5HT1A, 5HT1C, and 5HT2) in the prefrontal cortex of postmortem brain obtained from 60 teenage suicide victims and 60 age and sex matched controls over a 4 year period. In addition, we will also determine 5HT1A receptors in the hippocampus brain region. In order to determine whether or not postreceptor dysregulation and alteration in the phosphoinositide (PI) signal transduction mechanism is associated with suicide, we will study inositol 1,4,5 Triphosphate (IP3) and protein kinase C (PKC) receptors which are receptors for second messengers of the PI signalling system. In addition to comparing these biochemical measures of suicide victims to normal controls, we will examine the relationship between the above receptor measures and the presence of psychopathology, substance abuse, alcoholism, severity of illness, and violent means of suicide among the suicide victims. We will also examine the relationship between family history of psychopathology and the receptor indices in the suicide victims. We will perform psychological autopsies on the suicide victims and controls and psychological assessments of family members to determine the presence and/or absence of psychopathology, substance abuse, and suicidal behavior. The Specific Aims of our proposal are to examine whether or not serotonin receptor subtypes and second messenger (IP3 and PKC) receptors are different in the postmortem brain of suicide victims as compared to control subjects, and whether or not they are related to a history of psychopathology in suicide victims or to a family history of psychopathology and substance abuse. We hypothesize that 5HT receptor subtypes will be abnormal in suicide victims, such that 5HT2 and 5HT1C receptors will be increased in cortex and 5HT1A receptors increased in hippocampus but not in cortex. We also hypothesize a postreceptor dysregulation of the PI signalling system in the brain of suicide victims. A better understanding of the pathophysiology of suicidal behavior may aid in the identification, treatment and prevention of suicide among youths.